Program Director/Principal Investigator (Last, First, Middle): Significance: Alzheimer?s disease (AD) is the most common cause of dementia. By 2050, the cost of treating AD in the US is expected to increase to $1.1 trillion a year from the current $200 billion. Obviously, new therapeutic approaches for treating AD are essential. Data from active and passive immunizations trials had shown that in immunized AD patients the highest anti-A? antibody titers correlated with a reduction in brain pathology, suggesting that pathology-modifying benefits (Clinical Dementia Rating - Sum of Boxes and Mini Mental State Examination scores) were closely linked to the antibody titers. Rationale: Due to the enormous costs associated with the long-term passive immunotherapy, we believe that it is critical to develop a safe and immunogenic active vaccine targeting simultaneously two disease-related post-translationally modified proteins (PTM) involved in the pathogenesis of AD. Importantly, we plan to compare the therapeutic efficacy of well- characterized unmodified B cell epitopes of A? and tau that have shown efficacy in transgenic models of AD with PTM A? and tau that occur early in AD pathogenesis. Innovation: We have developed a universal MultiTEP platform and showed that it is extremely immunogenic in inbred mice of different immune haplotypes, as well as in outbred rabbits and monkeys. We have also identified a novel safe adjuvant, AdvaxCpG that has previously been used in human clinical trials, which provides additional immune enhancement for the MutiTEP- based anti-A?, Tau, and ?-syn vaccines. Finally, we have modified our MultiTEP platform by incorporating click chemistry to generate conjugate vaccines targeting several PTM molecules involved in AD pathogenesis. Design: This study is based on the evidence that abnormal PTM A? and tau play an important role in the onset and progression of AD making them attractive targets for active immunotherapy. Based on the literature we have chosen A?pE3, A?pE11, pTau202/205, pTau396/404, and pTau422 B cell epitopes that we attached to modified MultiTEP platform. These adjuvanted vaccines designed for clinical trials can potentially (i) activate a broad repertoire of nave and memory Th cells specific to MultiTEP; (ii) generate high titers of antibodies specific to only PTM proteins, but not native molecule, and (iii) they can?t generate potentially harmful autoreactive Th cells or induce high titers of unfavorable anti-MultiTEP antibodies. We suggest that (i) vaccines targeting PTM can be more effective than that targeting unmodified species of tau and A?; (ii) vaccines targeting simultaneously two pathological proteins, A? and tau, could be more therapeutically effective than targeting a single protein. To test these hypotheses we will evaluate the immunogenic and therapeutic efficacy of multiple MultiTEP vaccines in three complementary Aims using pathologically robust A? (5XFAD), tau (THY-Tau22), and the bigenic 5XFAD crossed to THY-Tau22 (T5x) mouse models. The following Specific Aims will be explored to determine the best candidate vaccines. If successful, this strategy will form the basis of future clinical trials for AD. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page